Project Summary/Abstract Dementia represents one of the most important public health concerns to affect us in the coming decades. Among the most important research goals will be to identify the earliest, most reliable and easily obtainable markers of degeneration, because early identification of individuals most likely to decline now represents the most promising window for therapeutic interventions. We propose to examine pupillary responses as a novel early biomarker of Alzheimer's disease (AD) pathogenesis and staging. Unlike neuroimaging and cerebrospinal fluid (CSF) biomarkers, pupillary responses can be measured in as little as 5 minutes using a minimally-invasive, inexpensive, simple handheld device that could potentially enjoy widespread utility for screening in the context of a typical doctor's office visit. Pupil dilation recorded during simple cognitive tasks (e.g., digit span) provides a biomarker of the extent of cognitive effort or resource allocation required to achieve a given test score. Pupillary responses may be more sensitive to cognitive decline, because clinically meaningful declines in test scores become manifest only when the capacity to compensate is exceeded. If one person requires more effort to achieve the same score as another, that person is likely to be closer to maximum compensatory capacity and, therefore, is at higher risk for decline. Equally important, pupillary responses reflect locus coeruleus (LC) functioning, and postmortem studies implicate the LC as an early site of AD pathogenesis and degenerative changes with disease progression. Thus, pupillary responses may serve as a specific biomarker of functional alterations in a brain system affected by the earliest manifestations of AD. The proposed study will evaluate a model of LC system alterations across the aging-mild cognitive impairment (MCI)-AD continuum using (1) an innovative pupillometric evaluation of the functional integrity of the LC system, (2) examination of the structural integrity of the LC using recently-developed novel MRI methods, (3) a panel of CSF AD biomarkers (A?, P-tau, and total tau) anchoring participants to the existing pathophysiology involved in AD progression, and (4) innovative diagnostic and staging approaches to characterize the timeline of changes across the aging-MCI-AD continuum. Specifically, we propose to record pupillary responses during cognitive tasks, collect gold-standard CSF biomarkers of AD, and use an innovative MRI methodology to visualize neuromelanin-containing LC nuclei in 128 cognitively-normal (CN) individuals, 64 participants with amnestic MCI (aMCI), and 20 with AD. The specific aims are to determine whether pupillary responses are associated with early risk and staging of AD and whether pupillary responses are associated with LC neuronal degeneration on MRI across the aging-MCI-AD continuum. We predict that the relationship between pupillary responses and risk and progression of AD will be curvilinear following an inverted-U function, such that preclinical individuals at greater risk for AD and aMCI individuals will show compensatory effort (greater pupil dilation), but with advancing disease and greater LC dysfunction, compensatory capacity will be overloaded, resulting in decline in pupil dilation in AD.